The primary cause of illness and death in patients with cystic fibrosis (CF) is progressive lung disease. CF is caused by a mutation in a chloride channel gene. Defective clearance of airway mucus related to the underlying chloride channel abnormality predisposes patients with CF to chronic airway infection and inflammation which in turn causes progressive airway damage. It is now well established that CF lung disease begins in infancy, frequently prior to the onset of symptoms, providing a rationale for early intervention. Inhaled hypertonic saline (HS) has been shown in short-term studies to improve mucociliary clearance and in long term studies to improve lung function, decrease the rate of pulmonary exacerbations and improve quality of life in CF patients over 6 years of age. There are no efficacy data in younger CF patients. HS is a particularly attractive agent to study in infants because it improves defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation. This proposal is for a randomized, controlled trial to assess the efficacy and safety of 7% HS inhaled twice daily for 48 weeks among infants with CF 4 to 15 months of age at enrollment. Our primary hypothesis is that, compared to the control agent (isotonic saline), HS will improve hyperinflation and obstructive lung disease as measured by infant lung function testing. The efficacy and safety results generated by the proposed trial may for the first time provide evidence for early initiation of a therapy used widely in older CF patients, thereby potentially delaying or preventing devastating airway damage before it becomes irreversible. One hundred and fifty infants ages 4 to 15 months will be enrolled at 16 centers. Study visits will take place at enrollment and weeks 4, 12, 24, 36 and 48, generally in conjunction with routine CF clinic visits. Subjects will undergo lung function testing at enrollment, 24 and 48 weeks. The primary endpoint is the change in the functional residual capacity, a measure of hyperinflation, from baseline to end of treatment. Additional lung function measures will also be assessed. The secondary endpoint is the time to first pulmonary exacerbation requiring antibiotic therapy. Other clinical endpoints will include changes in weight and height, resting respiratory rate and oximetry, a standardized cough score, and symptoms by parental home report. Safety will be assessed by evaluation of rates of adverse events, withdrawal, adherence to treatment, new isolation of CF pathogens from respiratory cultures;and clinical parameters measured at study visits during the 48-week treatment period. This Clinical Coordinating Center application is submitted in conjunction with a Data Coordinating Center application. This is the lead application. The public health impact of this study could be significant, as it may provide the first efficacy and long term safety data on hypertonic saline in infants with CF, potentially allowing the use of this promising agent in the youngest CF patients. HS is a particularly attractive agent to study in infants because it improves defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation. This would be the first multicenter clinical trial of a pulmonary maintenance therapy specifically in infants with CF, and the first to use measures of infant lung function as an endpoint.
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